Linked Life Data

11776408

Source:http://linkedlifedata.com/resource/pubmed/id/11776408

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2002-1-3
pubmed:abstractText
PK2 is a polymeric anticancer conjugate composed of an N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer backbone and pendant doxorubicin (DOX) linked via a Gly-Phe-Leu-Gly peptide spacer. Additionally galactose residues are present to facilitate liver targeting. To justify clinical evaluation of PK2 it was necessary to determine its late cardiotoxicity compared to that of free DOX. A well standardised Sprague-Dawley rat model was used with either intravenous (i.v.) administration (4, 8 and 12 mg/kg DOX equivalent) or intraperitoneal (i.p.) administration (12, 18, 24 and 36 mg/kg DOX equivalent) of PK2. This variation in the route was due to the limited solubility of PK2 at higher doses. PK2 showed two to three times less acute toxicity (assessed by the maximum reduction in body weight in the first 2 weeks) than free DOX, and both compounds were less toxic when given i.p.. No animals given PK2 i.v. showed clinical signs of cardiotoxicity, the only toxicity seen was abnormal tooth growth (approximately 50% of the animals receiving 12 mg/kg, DOX equivalent). In contrast, several animals receiving free DOX (1-4 mg/kg) i.v. died due to cardiotoxicity in an approximately dose-related manner. All animals receiving free DOX (4 mg/kg) died by 12 weeks. Following i.p. administration of PKZ there were only two late deaths related to cardiotoxicity and these were in the 24 mg/kg DOX equivalent group. All animals receiving PK2 at the highest dose (36 mg/kg DOX equivalent) died within 4 weeks, cardiotoxicity was not the main contributing factor. In this study, PK2 displayed a approximately 5-fold reduction in cardiotoxicity relative to free DOX and this supported the progression of PK2 into early clinical investigation.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0960-3271
pubmed:author
pubmed:issnType
Print
pubmed:volume
20
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
461-70
pubmed:dateRevised
2011-11-17
pubmed:meshHeading
pubmed:year
2001
pubmed:articleTitle
Preclinical evaluation of the cardiotoxicity of PK2: a novel HPMA copolymer-doxorubicin-galactosamine conjugate antitumour agent.
pubmed:affiliation
Normal Tissue Radiobiology Group, Research Institute (University of Oxford), The Churchill Hospital, UK.
pubmed:publicationType
Journal Article, Comparative Study